The present invention relates to a gastrointestinal mucosa-adherent matrix adapted to stay long in the gastrointestinal tract for sustained drug release, a pharmaceutical preparation based on the matrix, and a coating composition which renders dosage forms adherent to the mucosa.
Controlled-release drug delivery systems, particularly sustained-release preparations, are advantageous in that they help to reduce the frequency of administration of a drug without detracting from the effect of medication, prevent any sudden elevation of the blood concentration of the drug to reduce the risk of side effects, and maintain a therapeutically effective blood concentration for an extended period of time. Therefore, much research has been undertaken in the field of controlled release technology from the aspects of active drug, formulation and dosage form. By way of illustration, there are known an encapsulated preparation such that a core containing an active ingredient is covered with a shell, and a matrix type preparation such that an active ingredient has been dispersed in a release-controlling layer. These preparations are generally provided in such dosage forms as tablets, capsules and granules.
Meanwhile, many drug substances are absorbed mostly from the small intestine and, to a lesser extent, from the large intestine. Moreover, in humans, reportedly it takes about 5 to 6 hours for an orally administered drug to reach the large intestine.
However, in oral administration, the residence time of the drug in the digestive canal is of necessity limited even if its release is critically controlled by a sophisticated controlled release system, so that the drug is not efficiently absorbed but is excreted from the body without being fully utilized. Furthermore, in the case of a drug substance which acts directly and locally to produce the expected effect, it is likewise excreted without being utilized if the duration of contact is short. Particularly in cases in which the drug substance is sparingly soluble, its pharmacologic actions cannot be effectively utilized. Therefore, in the conventional drug delivery systems, it is difficult to insure absorption of active ingredients beyond a limited time period.
European Patent Publication No. 0368247A3 discloses a matrix preparation such that a pharmaceutically active ingredient is dispersed in a polyglycerol fatty acid ester-based matrix which is solid at ambient temperature. Moreover, European Patent Publication No. 0406856A2 discloses an FGF protein composition which is a granulated preparation using a polyglycerol fatty acid ester. Furthermore, European Patent Publication No. 0455391 proposes a granulated preparation prepared by thermal fluidization of a particulate composition containing a granular polyglycerol fatty ester having a melting point of 40 to 800xc2x0 C. and an active ingredient.
However, none of these prior art literature teach or suggest a pharmaceutical preparation having a gastrointestinal mucosa-adherent property.
It is an object of the present invention to provide a gastrointestinal mucosa-adherent matrix adapted to attach itself to the gastrointestinal mucosa to thereby remain within the gastrointestinal tract for a long period of time and promote absorption of the active ingredient for improved bioavailability.
It is another object of the invention to provide a gastrointestinal mucosa-adherent matrix adapted to attach itself to a specific site within the gastrointestinal tract to thereby allow an active ingredient to act directly on the living body.
It is still another object of the invention to provide a gastrointestinal mucosa-adherent matrix which allows even a sparingly water-soluble active ingredient to be effectively utilized by the body.
A further object of the invention is to provide a pharmaceutical preparation having the above-mentioned beneficial characteristics.
Yet another object of the invention is to provide a coating composition which renders a drug substance or dosage form adherent to the gastrointestinal mucosa.
The inventors of the present invention found that the duration of action of various active ingredients can be prolonged by incorporating a certain substance having the property to become viscous on contact with water (hereinafter referred to as xe2x80x9cviscogenic agentxe2x80x9d) in a pharmaceutical composition or coating a pharmaceutical composition with such a viscogenic agent. The present invention has been completed based on these findings.
Thus, the present invention provides a gastrointestinal mucosa-adherent matrix which is solid at ambient temperature, and which contains a viscogenic agent as dispersed at least in the neighborhood of the surface layer of a matrix particle containing a polyglycerol fatty acid ester and/or a lipid and an active ingredient.
The above gastrointestinal mucosa-adherent matrix which is solid at ambient temperature includes a matrix in which each matrix particle containing a polyglycerol fatty acid ester and/or a lipid and an active ingredient has a coating layer comprising or containing the viscogenic agent.
The present invention further provides a solid pharmaceutical preparation based on the matrix, which may be in the form of fine granules or granules.
The present invention further provides a coating composition comprising at least the viscogenic agent. The coating composition may further contain at least one member selected from the group consisting of polyglycerol fatty acid esters, lipids, enteric polymers and water-insoluble polymers.
As used throughout this specification, the term xe2x80x9cgastrointestinal mucosa-adherentxe2x80x9d refers to any and all cases in which the property of adhering to the gastrointestinal mucosa is exhibited or imparted by the viscogenic agent, including cases in which the matrix additionally has an enteric or gastric coating layer which does not contain the viscogenic agent. The term xe2x80x9cthe neighborhood of the surface layerxe2x80x9d means not only the surface of the matrix particle but also the region adjoining to the surface, including a coating layer such as the one mentioned above.
The term xe2x80x9ccoatingxe2x80x9d is used herein to mean not only a process in which the whole surface of a matrix particle is covered with a coating composition containing the viscogenic agent but also a process in which the surface of the matrix particle is partially covered with such a coating composition.
It should also be understood that where the matrix and/or the polyglycerol fatty acid ester or the like is a mixture, the composition does not show a distinct melting point but softens at a specific temperature. The term xe2x80x9cmelting pointxe2x80x9d as used in this specification includes the softening point displayed by such a mixture.
The viscogenic agent used in the present invention may be any substance that develops a sufficient degree of viscosity in the presence of water to adhere to the gastrointestinal mucosa and is pharmaceutically acceptable. Preferred species of the viscogenic agent swell or gain in viscosity to a remarkable extent on contact with water. As examples of such viscogenic agent, there may be mentioned polymers containing carboxyl groups or salts thereof, cellulose ethers, polyethylene glycols having molecular weights not less than 200,000, and naturally-occurring mucous substances. The preferable viscogenic agents are those having a viscosity in the range of 3 to 50,000 cps, preferably 10 to 30,000 cps, and more preferably 15 to 30,000 cps as a 2 percent by weight aqueous solution thereof at 20xc2x0 C. When a polymer becomes viscous by neutralization, the viscosity of a 0.2 percent by weight aqueous solution of the viscogenic agent is, for example, in the range of 100 to 500,000 cps, preferably 100 to 200,000 cps, and more preferably 1,500 to 100,000 cps at 20xc2x0 C. In the present invention, at least one of such viscogenic agents is employed, and needless to say, two or more species of said viscogenic agents may be employed in combination.
The polymers containing carboxyl groups or salts thereof include, for example, acrylic acid polymers obtainable by polymerization of a monomer containing acrylic acid and salts thereof as a monomer component. The salts may be the corresponding salts of monovalent metals such as sodium, potassium, and the like and of divalent metals such as magnesium, calcium, and the like. Such acrylic acid polymers and salts preferably contain 58.0 to 63.0 percent by weight of carboxyl groups and have molecular weights of 200,000 to 6,000,000 and preferably 1,000,000 to 5,000,000. The preferred acrylic polymers include an acrylic acid homopolymer or a salt thereof. Such polymers are described as carboxyvinyl polymers in the Formulary on Non-official Drugs (October, 1986). As specific examples of polymers in this category, there may be mentioned carbomers [Trade name: Carbopol (hereinafter referred to as Carbopol), The B. F. Goodrich Company] 910, 934, 934P, 940, 941, 1342 (NF XVII) , etc., HIVISWAKO 103, 104, 105 (Trade name of Wako Pure Chemical Industries, Japan), NOVEON AA1 (Trade name of The B. F. Goodrich Company), Calcium Polycarbophil (USP XXII) and so on.
The cellulose ethers mentioned above include, for example, carboxymethylcellulose sodium (sometimes referred to briefly as CMC-sodium) (The Pharmacopoeia of Japan (hereinafter referred to as J.P.) XI ], hydroxypropylmethylcellulose 2208, 2906 [e.g. HPMC-65SH50, HPMC-65SH4000 (Trade name of Shin-Etsu Chemical Co., Ltd., Jaan)], 2910 [e.g. TC-5 (Trade name of Shin-Etsu Chemical Co., Ltd., Japan)] (J.P. X), methylcellulose, crystalline cellulose-carboxymethylcellulose sodium (e.g. Avicel RC) (the Formulary of Non-official Drugs) and so on.
The naturally-occurring mucous substances include, for example, mucin, agar, gelatin, pectin, carrageenan, sodium alginate, locust bean gum, xanthan gum, tragacanth gum, arabic gum, chitosan, pullulan, waxy starch and so on.
Preferred viscogenic agents contain at least one of the acrylic acid polymers and salts thereof. Particularly preferred viscogenic agents are acrylic acid polymers and salts thereof.
The polyglycerol fatty acid esters are esters of polyglycerols with fatty acids and may be monoesters, diesters or polyesters. The polyglycerol fatty acid esters show no crystal polymorphism and are characterized in that they hardly interact with pharmacologically active ingredients. Therefore, the ingredient in the presence of a polyglycerol fatty acid ester is deactivated only slightly and remains stable for a long time.
Polyglycerol is a xe2x80x9cpolyhydric alcohol containing each molecule n (cyclic form) to n+2 (straight or branched form) hydroxyl groups and nxe2x88x921 (straight or branched form) to n (cyclic form) ether bondsxe2x80x9d [xe2x80x9cPolyglycerin Esterxe2x80x9d, edited by Sakamoto Yakuhin Kogyo Co., Ltd., Japan, published May 2, 1986, page 12] and the compound of the following formula (I), for instance, can be employed. 
wherein n represents the degree of polymerization which is an integer of not less than 2.
In the above formula, n is generally 2 to 50 preferably 2 to 20, and more preferably 2 to 10. The polyglycerols need not be straight-chain but may be branched.
Typical examples of such polyglycerol are diglycerol, triglycerol, tetraglycerol, pentaglycerol, hexaglycerol, heptaglycerol, octaglycerol, nonaglycerol, decaglycerol, pentadecaglycerol, eicosaglycerol, triacontaglycerol and so on. Of these species of polyglycerol, tetraglycerol, hexaglycerol and decaglycerol are used most frequently.
The fatty acids include, for example, saturated or unsaturated higher fatty acids containing 8 to 40 carbon atoms, preferably 12 to 22 carbon atoms. Thus, for example, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, myristic acid, lauric acid, ricinoleic acid, caprylic acid, capric acid, behenic acid, etc. may be mentioned. Among these fatty acids, for example, stearic acid, oleic acid, lauric acid, ricinoleic acid and behenic acid are preferred.
As specific examples of such polyglycerol fatty acid ester, there may be mentioned behenyl hexa(tetra)glyceride, caprylyl mono(deca)glyceride, caprylyl di(tri)glyceride, capryl di(tri)glyceride, lauryl mono(tetra)glyceride, lauryl mono(hexa)glyceride, lauryl mono(deca)glyceride, oleyl mono(tetra)glyceride, oleyl mono(hexa)glyceride, oleyl mono(deca)glyceride, oleyl di(tri)glyceride, oleyl di(tetra)glyceride, oleyl sesqui(deca)glyceride, oleyl penta(tetra)glyceride, oleyl penta(hexa)glyceride, oleyl deca(deca)glyceride, linolyl mono(hepta)glyceride, linolyl di(tri)glyceride, linolyl di(tetra)glyceride, linolyl di(hexa)glyceride, stearyl mono(di)glyceride, stearyl mono(tetra)glyceride, stearyl mono(hexa)glyceride, stearyl mono(deca)qlyceride, stearyl tri(tieitra)glyceride, stearyl tri(hexa)glyceride, stearyl sesqui(hexa)glyceride, stearyl penta(tetra)glyceride, stearyl penta(hexa)glyceride, stearyl deca(deca)glyceride, palmityl mono(tetra)glyceride, palmityl mono(hexa)glyceride, palmityl mono(deca)glyceride, palmityl tri(tetra)glyceride, palmityl tri(hexa)glyceride, palmityl sesqui(hexa)glyceride, palmityl penta(tetra)glyceride, palmityl penta(hexa)glyceride, palmityl deca(deca)glyceride and so on.
Preferred polyglycerol fatty acid esters include, for example, behenyl hexa(tetra)glyceride (e.g. Riken Vitamin Co., Ltd., Japan; Poem J-46B, etc.), stearyl penta(tetra)glyceride (e.g. Sakamoto Yakuhin Kogyo Co., Ltd., Japan: PS-310), stearyl mono(tetra)glyceride (e.g. Sakamoto Yakuhin Kogyo Co., Ltd., Japan; MS-310), stearyl penta(hexa)glyceride (e.g. Sakamoto Yakuhin Kogyo Co., Ltd., Japan; PS-500), stearyl sesqui(hexa)glyceride (e.g. Sakamoto Yakuhin Kogyo Co., Ltd., Japan; SS-500) and stearyl mono(deca)glyceride, as well as mixtures thereof.
These polyglycerol fatty acid esters may be used either singly or in combination.
The molecular weight of the polyglycerol fatty acid ester is generally about 200 to 5000, preferably about 300 to 2000 and more preferably about 500 to 2000. The HLB (hydrophile-lipophile balance) number of the polyglycerol fatty acid esters is generally 1 to 22, preferably 1 to 15 and more preferably 2 to 9. The HLB number may be adjusted by using two or more polyglycerol fatty acid esters having different HLB numbers in combination. By varying the HLB number of polyglycerol fatty acid esters, the release and dissolution rates of the active ingredient can be controlled as desired.
While polyglycerol fatty acid esters can be selectively used according to the active ingredient, viscogenic agent and matrix form chosen, those which are solid at ambient temperature (about 15xc2x0 C.) are employed. The melting point of the polyglycerol fatty acid ester may for example be about 15 to 80xc2x0 C., preferably about 30 to 75xc2x0 C. and more preferably about 45 to 75xc2x0 C.
When two or more polyglycerol fatty acid esters are used as a mixture, one or more of the esters may be liquid provided that the matrix is solid at ambient temperature.
The lipid as a constituent of the matrix is one having a melting point of 40 to 120xc2x0 C., preferably 40 to 90xc2x0 C.
Typical examples of the lipid include, for example, saturated fatty acids containing 14 to 22 carbon atoms (e.g. myristic acid, palmitic acid, stearic acid, behenic acid, and the like) and salts thereof (e.g. the corresponding sodium and potassium salts), higher alcohols containing 16 to 22 carbon atoms (e.g. cetyl alcohol, stearyl alcohol, and the like), glycerol fatty acid esters such as monoglycerides, diglycerides and triglycerides of said fatty acids (e.g. 1-monostearin, 1-monopalmitin, and the like), oils (e.g. castor oil, cottonseed oil, soybean oil, rapeseed oil, beef tallow and other hardened oils), waxes (e.g. beeswax, carnauba wax, sperm wax, and the like), hydrocarbons (e.g. paraffin, microcrystalline wax, and the like), phospholipids (e.g. hydrogenated lecithin and the like) and so on. Preferred, among these lipids, are hydrogenated cottonseed oil, hydrogenated castor oil, hydrogenated soybean oil, carnauba wax, stearic acid, stearyl alcohol and microcrystalline wax.
There is no particular limitation on the type of active ingredient. The active ingredient in the present invention includes not only medicaments for human beings but also veterinary drugs. Thus, for example, central nervous system drugs such as antipyretic-analgesic-antiinflammatory agents, hypnotics and sedatives, antlepileptics, antivertigo agents, psychotropic agents, and the like; peripheral nervous system drugs such as skeletal muscle relaxants, autonomic drugs, antispasmodics, and the like; cardiovascular drugs such as cardiotonics, antiarrhythmic agents, diuretics, antihypertensive agents, vasodilators, vasoconstrictors, and the like; respiratory organ drugs such as bronchodilators, antitussives, and the like; digestive organ drugs such as antipeptic ulcer agents, digestants, intestinal function-controlling agents antacids, and the like; hormones; antihistaminics; metabolic drugs such as vitamins; antiulcer drugs; antibiotics; chemotherapeutic agents; and the like may be mentioned.
Since the matrix composition of the present invention adheres to the gastrointestinal mucosa, a sparingly water-soluble active ingredient can be used effectively.
Among specific examples of the active ingredient are indomethacin, salicylic acid, trepibutone, amoxanox, aspirin, valproic acid, ketoprofen, ibuprofen, probenecid, 3,4-dihydro-2,8-diisopropyl-3-thioxo-2H-1,4-benzoxazine-4-acetic acid (hereinafter, AD-5467), isosorbide dinitrate, vinpocetine, estazoram, acetazolamide, papaverine, tolbutamide, acetohexamide, verapamil, quinidine, morphine, buprenorphine hydrochloride, dihydrocodeine phosphate, ephedrine, scopolamine, chlorpromazine, manidipine hydrochloride, phenylpropanolamine hydrochloride, chlorpheniramine maleate, phenylephrine hydrochloride, procainamide hydrochloride, sulfanylamide, molsidomine, sulfadiazine, diazepam, quinidine, N-ethyl-N-demethyl-8,9-anhydroerythromycin A 6,9-hemiketal, epinephrine, reserpine, acetaminophen, theophylline, caffeine, cefalexin, ampicillin, sulfisoxazole, delapril hydrochloride, ipriflavone, 2,2xe2x80x2-[(2-aminoethyl)imino]di-ethanol bis(butylcarbamate) dihydrochloride, cefotiam hexetil hydrochloride, cyclandelate, idebenone [namely, 2-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone], propranolol, haloperidol, chlorothiazide, hydrochlorothiazide, sucralfate, vitamins such as riboflavin, ascorbic acid, and the like, minerals, amino acids and so on.
Preferred examples of the active ingredient used in this invention include antiulcer agents and therapeutic agents for gastritis. Typical examples of such antiulcer agents include 2-[(2-pyridyl)methylthio] benzimidazole and its derivatives (there hereinafter may be referred to briefly as benzimidazole compounds) and salts thereof. Among these benzimidazole compounds are the compounds described in Japanese Patent Publication No. 44473/1990 corresponding to U.S. Pat. No. 4,628,098, Japanese Patent Publication No. 38247/1991, and Japanese Patent laid open No. 173817/1991 corresponding to U.S. Pat. No. 5,013,743. To be specific, the compounds of the following formula (II) and physiologically acceptable salts thereof are particularly preferred. 
wherein R1 means hydrogen, an alkyl, a halogen, cyano, carboxy, an alkoxycarbonyl, an alkoxycarbonylalkyl, carbamoyl, a carbamoyalkyl, hydroxy, an alkoxy, a hydroxyalkyl, trifluoromethyl, an acyl, carbamoyloxy, nitro, an acyloxy, an aryl, an aryloxy, an alkylthio or a alkylsufinyl; R2 means hydrogen, an alkyl, acyl, an alkoxycarbonyl, carbamoyl, an alkylcarbamoyl, a dialkylcarbamoyl, an alkylcarbonylmethyl, an alkoxycarbonylmethyl or an alkylsulfonyl; R3 and R5 may be the same or different and each means hydrogen, an alkyl, an alkoxy or an alkoxyalkoxy; R4 means hydrogen, an alkyl, an alkoxy which may be fluorinated, an alkoxyalkoxy, an alkenyloxy which may be fluorinated or an alkynyloxy which may be fluorinated and m means an integer of 0 to 4.
The compound of the formula (II) can be produced by the processes described in the above patent literature or any process analogous thereto.
The substituents on the compound of the formula (II) are now briefly described.
Referring to R1 in the above formula, said alkyl includes an alkyl group of 1 to 7 carbon atoms; the alkoxy of said alkoxycarbonyl includes an alkoxy group of 1 to 4 carbon atoms; the alkoxy of said carbomoylalkyl includes an alkoxy group of 1 to 4 carbon atoms and the alkyl thereof includes an alkyl group of 1 to 4 carbon atoms; the alkyl of said carbomoylalkyl includes an alkyl group of 1 to 4 carbon atoms; said alkoxy includes an alkoxy group of 1 to 5 carbon atoms; the alkyl of said hydroxyalkyl includes an alkyl group of 1 to 7 carbon atoms; said acyl includes an acyl group of 1 to 4 carbon atoms; the acyl of said acyloxy includes an acyl group of 1 to 4 carbon atoms; said aryl includes phenyl; the aryl of said aryloxy includes phenyl; the alkyl of said alkylthio includes an alkyl group of 1 to 6 carbon atoms; and the alkyl of said alkylsulfinyl includes an alkyl group of 1 to 6 carbon atoms.
As represented by R2, said alkyl includes an alkyl group of 1 to 5 carbon atoms; said acyl includes an acyl group of 1 to 4 carbon atoms; the alkoxy of said alkoxycarbonyl includes an alkoxy group of 1 to 4 carbon atoms; the alkyl of said alkylcarbamoyl includes an alkyl group of 1 to 4 carbon atoms; the alkyl of said dialkylcarbamoyl includes an alkyl group of 1 to 4 carbon atoms; the alkyl of said alkylcarbonylmethyl includes an alkyl group of 1 to 4 carbon atoms; the alkoxy of said alkoxycarbonylmethyl includes an alkoxy group of 1 to 4 carbon atoms; and the alkyl of said alkylsulfonyl includes an alkyl group of 1 to 4 carbons.
The alkyl group for R3, R4 and R5 includes an alkyl group of 1 to 4 carbon atoms; the alkoxy includes an alkoxy group of 1 to 8 carbon atoms; and the alkoxy of said alkoxyalkoxy includes an alkoxy group of 1 to 4 carbon atoms.
Referring to R4, the alkoxy of said alkoxy which may be fluorinated includes an alkoxy group of 1 to 8 carbon atoms, the alkenyl of said alkenyloxy which may be fluorinated includes an alkenyl group of 2 to 6 carbon atoms; and the alkynyl of said alkynyloxy which may be fluorinated includes an alkynyl group of 2 to 6 carbon atoms. When the alkoxy, alkenyl or alkynyl group includes fluorinated, the preferred number of substitutions is 1 to 9.
The physiologically acceptable salt of the compound (II) include the corresponding hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate and so on. These salts can be prepared from the compound of formula (II) by a routine procedure.
The preferred substituents on the compound of the formula (II) are as follows. R1 is hydrogen atom, fluorine atom, methoxy group or trifluoromethyl group and m=1. The substituent R2 is hydrogen atom, R3 is hydrogen atom or methyl group, R4 is a C1-4 alkoxy group, a 2-propenyloxy group or an allyl group, which may be fluorinated, R5 is hydrogen atom or methyl group. The preferred position of substitution for R1 is position-4 or position-5 and preferably position-5.
Among compounds of the formula (II), the compounds in which R1=R2=R5=H and R3=H or CH3 are preferred. Particularly preferred are compounds in which R4 is a fluorinated C1-4 alkoxy group. The compounds in which R1 =R2=R5=H and R3=CH3 having the fluorinated C1-4 alkoxy group as R4 include, among others, a compound having a 2,2,2-trifluoroethoxy as R4 (hereinafter the compound may be referred to briefly as AG 1777), a compound having a 2,2,3,3-tetrafluoropropoxy as R4 (hereinafter the compound may be referred to briefly as AG 1789), a compound having a 2,2,3,3,3-pentafluoropropoxy as R4 (hereinafter the compound may be referred to briefly as AG1776), a compound having a 2,2,3,3,4,4-hexafluorobutoxy as R4, a compound having a 2,2,3,3,4,4,4-heptafluorobutoxy as R4, and so on.
The benzimidazole compound of the formula (II), inclusive of a pharmacologically acceptable salt thereof, is a therapeutic drug for treating peptic ulcers which has gastric acid antisecretory activity as a main pharmacological action, and gastric mucosa-protecting activity as well. By using the benzimidazole compound or salt in the matrix or solid preparation of the present invention, there can be obtained a more effective therapeutic regimen for treating peptic ulcer.
The active ingredient may be a peptide or a protein. Examples of such a peptide and protein include physiologically active peptides and hormones such as insulin, vasopressin, interferons, IL-2, urokinase, serratiopeptidase, superoxide dismutase (SOD), thyrotropin releasing hormone (TRH), luteinizing hormone releasing hormone (LH-RH), corticotropin releasing hormone (CRF), growth hormone releasing hormone (GHRH), somatostatin, oxytosin, growth hormone, and the like; growth factors such as epidermal growth factor (EGF), nerve growth factor (NGF), insulin-like growth factor (IGF), fibroblast growth factor (FGF) (e.g. aFGF, bFGF, etc.), erythropoietin (EPO); calcitonin, colony stimulating factor (CSF) and so on. bFGF includes rhbFGF muteins, such as CS23 (hereinafter referred to as TGP580; European Patent Publication No. 281822).
Due to their inherent properties, these active ingredients may vary in solubility and the site of absorption within the gastrointestinal tract. Generally speaking, the solubility of basic drugs is high on the acidic side and low on the alkaline side. Therefore, the rate of release of a basic active ingredient in a matrix or preparation is fast in the stomach where the ingredient passes first and the environment is acidic, while it is slow in the intestine where the environment is neutral to weakly alkaline. Conversely the solubility of an acidic drug is high on the alkaline side but low on the acidic side. Therefore, the rate of release of an acidic active ingredient in a matrix or preparation is fast in the intestine where neutral to weakly alkaline conditions prevail and slow in the stomach through which it passes in the first place.
Therefore, in order that an active ingredient may be released at a constant rate in both the stomach and intestine, irrespective of environmental pH, the matrix containing a polyglycerol fatty acid ester or a lipid and being solid at ambient temperature may contain a water-insoluble or sparingly water-soluble solid base together with an acidic active ingredient or an enteric polymer together with a basic active ingredient.
The acidic active ingredient includes various substances whose aqueous solutions, not in the form of salts, are acidic (e.g. pH 1.5 to 7.0, preferably 2.0 to 6.8). Among such acidic active ingredients are, for example, indomethacin, salicylic acid, AD-5467, trepibutone, amoxanox, aspirin, valproic acid, ketoprofen, ibuprofen, ascorbic acid, probenecid and so on. Among these acidic drugs, AD-5467, trepibutone and indomethacin are frequently used.
The solubility of the solid base in water may, for example, be not more than 0.1 g/ml, preferably not more than 0.001 g/ml, at 37 xc2x0 C. Solid bases of low solubility provide satisfactory results. As such solid bases, there may be mentioned the oxides, hydroxides, inorganic acid salts or organic acid salts of metals of Group I, II or III of Periodic Table of the Elements, such as magnesium oxide, magnesium hydroxide, magnesium silicate, magnesium carbonate, aluminum silicate, aluminum hydroxide, silicic acid (Syloid, Aerosil), magnesium metasilicate aluminate (Neusilin), magnesium stearate, calcium stearate, aluminum stearate, sodium stearate and so on. These solid bases may be used singly or in combination.
The particle size of such solid base is generally not more than about 50 xcexcm and preferably about 0.05 to 20 xcexcm. The proportion of the solid base to the total preparation is generally about 1 to 80 percent by weight, preferably about 1 to 50 percent by weight and more preferably about 10 to 30 percent by weight.
The basic active ingredient includes various components whose aqueous solutions, not in the form of salts but in free forms, are basic (for example pH 7.0 to 13.0, preferably pH 7.0 to 10.5). As such basic active ingredients, there may be mentioned vinpocetine, estazolam, acetazolamide, papaverine, tolbutamide, acetohexamide, verapamil, quinidine, morphine, ephedrine, scopolamine, chlorpromazine, manidipine and so on. Among these basic drugs, vinpocetine and acetazolamide are frequently employed.
The enteric polymer is a polymer which dissolves little in the stomach but dissolves in the intestine. Such enteric polymer is preferably an acidic polymer having a molecular weight of about 30,000 to 500,000, preferably about 70,000 to 400,000. As examples of such enteric polymer, there may be mentioned hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, carboxymethylethylcellulose (CMEC AQ, Trade name of Kohjin Co., Ltd., Japan), methacrylic acidmethyl methacrylate copolymers (Eudragit L100-55, L100and S100, Trade name of Rxc3x6hm Pharma GmbH, Germany) and so on. These enteric polymers are used singly or in combination. Among these enteric polymers, Eudragit L100-55 is one of the polymers which can be frequently employed.
The enteric polymer is preferably used in finely divided form. The particle size of such enteric polymer is generally not more than about 50 xcexcm and preferably about 0.05 to 10 xcexcm. The content of such enteric polymer based on the total composition is generally about 1 to 80 percent by weight, preferably about 1 to 50 percent by weight, and more preferably about 10 to 30 percent by weight.
The content of the active ingredient to, the whole matrix composition is about 0.0001 to 95 percent by weight and preferably about 0.1 to 90 percent by weight.
The matrix according to the present invention may be classified into (A) a matrix composition such that the viscogenic agent has been dispersed at least in the neighborhood of the surface layer of a matrix particle containing the active ingredient and the polyglycerol fatty acid ester, (B) a matrix composition such that the viscogenic agent has been dispersed in the neighborhood of the surface layer of a matrix particle containing the active ingredient and the lipid, and (C) a matrix composition such that the matrix particle has been coated with a coating composition comprising or containing the viscogenic agent.
The proportion of the polyglycerol fatty acid ester and/or lipid to be incorporated in each matrix particle is about 0.001 to 10,000 parts by weight and preferably about 0.001 to 50 parts by weight relative to a part by weight of the active ingredient.
The matrix particles of matrixes (A) and (C) each containing the polyglycerol fatty acid ester may give still more beneficial effects when a lipid is further incorporated. The lipid for this purpose is a pharmaceutically acceptable water-insoluble substance which is able to control the rate of dissolution of the active ingredient. Among such lipids are the compounds mentioned hereinbefore.
When used in combination with the polyglycerol fatty acid ester, the lipid can be used in a proportion which does not detract from the adhesiveness of the matrix to the gastrointestinal mucosa. Usually, the lipid is used in a proportion of about 0.01 to 100 parts by weight and preferably about 1 to 20 parts by weight relative to a part by weight of the active ingredient.
Unless contrary to the objects of the invention, various additives which are commonly used in the manufacture of solid pharmaceutical preparations, particularly fine granules or granules, may be added to the particles of matrixes (A), (B) and (C). The additives mentioned just above include various excipients such as lactose, corn starch, talc, crystalline cellulose (Avicel and the like), powder sugar, magnesium stearate, mannitol, light silicic anhydride, magnesium carbonate, calcium carbonate, L-cysteine, and the like; binders such as starch, cane sugar, gelatin, powdered gum arabic, methylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pullulan, dextrin, and the like; disintegrators such as carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, and the like; surfactants including anionic surfactants such as sodium alkylsulfates and the like and nonionic surfactants such as polyoxyethylene-sorbitan fatty acid esters, polyocyethylene-fatty acid esters and polyoxyethylene-castor oil derivatives, and the like; gastric antacids and mucosa-protecting agents such as magnesium hydroxide, magnesium oxide, aluminum hydroxide, aluminum sulfate, magnesium metasilicate aluminate, magnesium silicate aluminate, sucralfate, and the like; colorants; corrigents; adsorbents; preservatives; wetting agents; antistatic agents; disintegration retarders; and so on. The amounts of these additives can be selected as desired within the range not adversely affecting the adhesion of the final preparation to the mucosa.
The gastrointestinal mucosa-adherent matrixes (A), (B) and (C) according to the invention are solid at ambient temperature. The preferred melting point of these matrixes may for example be about 30 to 120xc2x0 C. and preferably about 40 to 120xc2x0 C.
Referring to the matrixes (A) and (B), the viscogenic agent may be dispersed throughout each matrix particle containing the polyglycerol fatty acid ester and/or lipid and the active ingredient or dispersed in a coating film covering the matrix particle. The viscogenic agent in the matrix becomes viscous on contact with water and probably because it bleeds out onto the surface of the matrix particle, the matrix is rendered adherent to the gastrointestinal mucosa. Therefore, the matrix of the invention is retained in the gastrointestinal tract for a long time during which the active ingredient is gradually dissolved within the gastrointestinal tract and absorbed. Furthermore, this matrix adheres efficiently to a specific site of the gastrointestinal mucosa. Therefore, when the active ingredient is such that its efficacy is dependent on direct exposure, the duration of contact with the desired site of action is prolonged so that the pharmacological activity of the ingredient can be made fully available over a sufficient time. Moreover, even a sparingly water-soluble active ingredient can be released gradually at a selected site within the gastrointestinal tract with the result that its efficacy can be made available over a protracted time period.
In the matrix particle of matrix (A) or of matrix (B), the proportion of the viscogenic agent is about 0.005 to 95 percent by weight, preferably 0.5 to 30 percent by weight, and more preferably about 1 to 10 percent by weight, based on the total weight of the matrix composition.
The matrix (A) composition may be manufactured by dispersing the viscogenic agent, polyglycerol fatty acid ester and active ingredient and the matrix (B) composition may be prepared by dispersing the viscogenic agent, lipid and active ingredient. By way of illustration, the solid matrix containing the polyglycerol fatty acid ester or lipid and which is solid at ambient temperature is melted by heating it at a temperature above its melting point, then the viscogenic agent and the active ingredient are added and dispersed therein and the mixture is cooled to give the matrix composition. The heating temperature for the matrix may, for example, be about 40 to 150xc2x0 C., preferably about 50 to 90xc2x0 C.
When the active ingredient is an acidic drug, the solid base mentioned hereinbefore may be advantageously added. When it is a basic drug, the enteric polymer mentioned hereinbefore may be added. In melting the polyglycerol fatty acid ester and/or lipid, the abovementioned additive may be melted together or these materials may be respectively melted and then combined. It is also possible to add the viscogenic agent and additive in particulate form together with the active ingredient.
Fine granules or granules containing said matrix can be manufactured by means of the conventional granulating machinery. Such fine granules and granules are preferably prepared under cooling. For example, it is a preferred practice to produce spherical fine granules by spray mist cooling, particularly by spray-chilling. Spray-chilling can be effected by dropping a molten matrix at a constant flow rate on a high-speed rotating disk driven at 10 to 6,000 rpm, preferably 900 to 6,000 rpm, and more preferably 1,000 to 3,000 rpm. The rotary disk for this purpose may be a circular plate disk, smooth circular plate, made of aluminum or the like material, which has a diameter of, for example, 5 to 100 cm, preferably 10 to 20 cm. The dropping speed of the molten matrix can be selected according to the desired particle size of fine granules and is generally about 2 to 200 g/minute and preferably about 5 to 100 g/minute. The resulting granules are closer to true spheres, indicating that a more uniform coating film can be efficiently formed by using the coating composition.
The matrix (A) or (B) can also be prepared by kneading the above-mentioned components with the aid of a solvent and granulating the resultant mass. In this case, the undesirable effect of heat on the active ingredient can be avoided. Therefore, even when the active ingredient is a peptide, a protein or the like, an effective matrix composition can be easily obtained, with the deactivation of the drug being held to a minimum.
The matrix particles of the matrix (C) need only have been coated with a coating composition containing at least said viscogenic agent. The coating composition may contain, in addition to the viscogenic agent, at least one member of said polyglycerol fatty acid ester, said lipid, said enteric polymer and a water-insoluble polymer. In this case, when the viscogenic agent is a substance which is poorly compatible or incompatible with the above-mentioned components, the matrix particle thus coated has a surface film in which said viscogenic agent has been well dispersed. The coating composition may further contain said active ingredient and/or said additives.
The water-insoluble polymer mentioned hereinbefore includes, for example, hydroxypropylmethylcellulose phthalate (J.P. XI), hydroxypropylmethylcellulose acetate succinate (Shin-Etsu Chemical Co., Ltd., Japan), carboxymethylethylcellulose (Freund Industrial Co., Ltd.; CMEC, the Formulary of Non-official Drugs 1986), cellulose acetate trimellitate (Eastman Co., Ltd.), cellulose acetate phthalate (J.P. XI), ethylcellulose (Asahi Chemical Industry Co., Ltd., Japan; FMC), aminoalkyl methacrylate copolymer (Rxc3x6hm Pharma; Eudragit E100, RS, RN100L, RSPML, RN100, RSPM), methacrylic acid copolymer L (Rxc3x6hm Pharma, Eudragit L100), methacrylic acid copolymer L-D (Rxc3x6hm Pharma, Eudragit L-30-D-55), methacrylic acid copolymer S (Rxc3x6hm Pharma; Eudragit S-100), polyvinyl acetate phthalate (COLOR-CON), Eudragit NE30-D (Trade name of Rxc3x6hm Pharma) and so on. These water-insoluble polymers can be used singly or in combination.
The proportion of the viscogenic agent based on the total nonvolatile matter of the coating composition is about 0.005 to 100 percent by weight, preferably about 0.05 to 95 percent by weight, more preferably about 0.5 to 30 percent by weight, and particularly about 1 to 10 percent by weight.
When the viscogenic agent is used in combination with at least one of polyglycerol fatty acid ester, lipid, enteric polymer and water-insoluble polymer, the proportion of the viscogenic agent is about 0.005 to 95 percent by weight, preferably about 0.5 to 30 percent by weight, and more preferably about 1 to 10 percent by weight based on the total nonvolatile matter of the coating composition.
In the coating composition may be incorporated two or more components selected from among said polyglycerol fatty acid ester, lipid, enteric polymer and water-insoluble polymer. When said polyglycerol fatty acid ester and/or lipid is used in combination with another component selected from among said enteric polymer and water-insoluble polymer, the preferred proportion of such other component to each part by weight of the polyglycerol fatty acid ester and/or lipid is about 0.0001 to 1,000 parts by weight, preferably about 0.01 to 100 parts by weight, and more preferably about 0.01 to 10 parts by weight.
The coating amount of the coating composition can be selected according to the type of solid preparation and the desired strength of adhesion to the mucosa. The coating amount relative to the solid preparation is about 0.1 to 30 percent by weight and preferably about 0.5 to 10 percent by weight for tablets, about 0.1 to 50 percent by weight and preferably about 1 to 20 percent by weight for pills and granules, and about 0.1 to 100 percent by weight and preferably about 1 to 50 percent by weight for fine granules.
In the coating procedure, the common additives mentioned hereinbefore may be incorporated in the coating composition or may be applied independently of the coating composition. The proportion of such additives to be added may for example be about 0.1 to 70 percent by weight, preferably about 1 to 50 percent by weight, more preferably about 20 to 50 percent by weight based on the nonvolatile matter of the coating composition.
Coating can be carried out by the conventional manner, such as pan coating, air-suspension or fluidized bed coating, centrifugal coating and so on. When the coating composition is a solution or dispersion containing water or an organic solvent, the spray-coating method can also be employed. The proportion of such water or organic solvent may for example be about 25 to 99 percent by weight. The type of organic solvent is not so critical. Thus, for example, alcohols such as methanol, ethanol, isopropyl alcohol, and the like; ketones such as acetone and the like; and halogenated hydrocarbons such as chloroform, dichloromethane, trichloroethane, and the like can be employed.
When the polyglycerol fatty acid ester and/or lipid is incorporated in the coating composition of the invention, a coated pharmaceutical product can be manufactured by melting the polyglycerol fatty acid ester and/or lipid, with or without addition of other additives, at an elevated temperature, emulsifying the molten mass with water, spraying the surface of the substrate preparation with the resulting emulsion and drying the coated preparation. An alternative method may comprise preheating the solid substrate preparation with a hot current of air in a coating pan or the like and feeding the coating composition to the pan so that it may melt and spread over the substrate preparation.
The coating of such a solid preparation is usually carried out at a temperature of 25 to 60xc2x0 C. and preferably 25 to 40xc2x0 C.
The coating time can be selected according to the coating method, the characteristics and amount of the coating composition and the characteristics of the substrate preparation, among other things.
Fine granules, granules, pills, tablets and other dosage forms can be rendered adherent to the mucosa by using the coating composition of the invention. The coating composition can be applied to a broad range of drug substances. For example, it can be applied not only to a matrix particle prepared by melting the polyglycerol fatty acid ester or lipid, and the like at an elevated temperature and adding an active ingredient thereto but also to a matrix particle containing a physiologically active peptide or protein which is easily deactivated by heat. A matrix particle containing such a thermolabile active ingredient can be manufactured by granulating the active ingredient and said additives, such as binder, excipient, disintegrator, and the like, together with said lipid where necessary, without using a polyglycerol fatty acid ester, at a low temperature not causing deactivation of the active ingredient. The matrix particle can also be manufactured by dispersing said components in water or an organic solvent with use of a kneader or the like and granulating the kneaded mass.
For all of the matrixes (A), (B) and (C), insofar as the viscogenic agent is allowed to exhibit its mucosal adhesivity in the gastrointestinal tract, the matrix may, where necessary, have an enteric or gastric coating or the like. For example, when the matrix has an enteric coating layer which is adapted to dissolve in the vicinity of the site of absorption, the matrix will adhere to the site of absorption to function as a target-oriented drug delivery system.
The solid preparation according to the present invention may be provided in a variety of dosage forms such as fine granules, granules, pills, tablets obtainable by compression-molding the fine granules or granules, and capsules obtainable by filling capsules with the fine granules or granules. Preferred dosage forms are fine granules and granules. The lipid-containing matrixes (A) and (C) are suitable for fine granules. The particle size distribution of the fine granules may, for example, be 10 to 500 xcexcm for 75 weight % or more of their total weight, more than 500 xcexcm for not more than 5 weight %, and less than 10 xcexcm for not more than 10 weight %. The preferred particle size distribution of the fine granules is 105 to 500 xcexcm for not less than 75 weight %, more than 500 xcexcm for not more than 5 weight %, and not more than 74 xcexcm for not more than 10 weight %. The particle size distribution of the granules may, for example, be 500 to 1410 xcexcm for not less than 90 weight % and not more than 177 xcexcm for not more than 5 weight %. The following examples and comparative example are merely intended to illustrate the present invention in further detail and should not be construed as defining the scope of the invention.